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PubMed2005

[Effects of sodium chloride on bone health].

This paper discusses the physiology of sodium effects on calcium metabolism and possible implications of increased salt intake on bone remodelling and bone mass. Osteoporosis is an increasing public health problem affecting more than 200 million of women around the world. The major complications of osteoporosis are fractures, which are frequently associated with high morbidity and mortality. A number of clinical, epidemiological and experimental studies aim at identifying lifestyle factors that may improve bone mass and prevent bone loss. Different nutrients are proposed to play a role in bone development during growth and in the maintenance of bone mass thereafter. However, the importance of sodium intake for bone health has not been elucidated. It is well known that high dietary sodium intake decreases renal calcium reabsorption, which in turn leads to a greater urinary calcium excretion. This effect has been demonstrated in studies in humans of all ages as well as in experimental animals. It is not clear to what extent sodium-induced calcium loss is compensated for by increased intestinal calcium absorption. It is suspected that, if not fully compensated, sustained hypercalciuria due to increased sodium intake may diminish bone mass. Postmenopausal women showed that increased dietary salt may indeed augment bone resorption. Sodium effects on bone mass in various studies are inconsistent and there is still no evidence that increased salt intake is a risk factor in the aetiology of osteoporosis A randomized longitudinal study of different sodium intake in two groups of subject could clarify the role of sodium in bone mass.

Animals↗
PubMed1991

Histological evaluation of cortical bone reaction to PMMA cement.

This study was designed to investigate histological changes in the tibia of adult mongrel dogs receiving PMMA bone cement in one tibial shaft and an inert filler, Bone wax, in the other. Sixteen dogs were used, 2 dogs were investigated at one week, 6 dogs at four weeks and 8 dogs at twelve weeks. It was shown in this study, that intramedullary implantation of PMMA bone cement leads to considerable impairment of bone remodelling. At each period of observation the index periosteal apposition/cortex thickness was lower on the cemented side; at 4 weeks an index of 0.42 (0.17-0.64) compared to 0.72 (0.42-0.91), and a 60-70 microns concentric fibrillar fibrous membrane was seen between cement and bone. On the Bone wax side few or no areas of fibrous tissue were detected at both 4 and 12 weeks; and when such tissue was present, islands of bone developing directly onto the wax was seen. The bone remodelling was impaired on the cemented side and limited to the outer half after 4 weeks.

Animals↗
PubMed1987

Acute myeloid leukemia and other myelopathic disorders following treatment with alkylating agents.

Several large cohorts of patients treated with alkylating agents served as a means to review the clinical and pathologic features of 55 cases of myelopathic disorders that resulted. The incidence was 1.8% overall and consisted of five patients (9.9%) who developed bone marrow hypoplasia or aplasia, 15 (27.2%) who developed a myelodysplastic syndrome, and 35 cases of acute myeloid leukemia (62.9%). The median time to recognition of MPD was 14 months, following cessation of chemotherapy. The distribution of the treatment-related MDS cases was different than "de novo" MDS with a high percentage of RAEB-T, and with the treatment related AMLs, there were a higher percentage of patients with FAB M6 (erythroleukemia), and no cases of FAB M3 (hypergranular promyelocytic). The median survival of all patients was very brief.

Adolescent↗
PubMed2000

Dual roles of Wnt signaling during chondrogenesis in the chicken limb.

Long bones of the appendicular skeleton are formed from a cartilage template in a process known as endochondral bone development. Chondrocytes within this template undergo a progressive program of differentiation from proliferating to postmitotic prehypertrophic to hypertrophic chondrocytes, while mesenchymal cells immediately surrounding the early cartilage template form the perichondrium. Recently, members of the Wnt family of secreted signaling molecules have been implicated in regulating chondrocyte differentiation. We find that Wnt-5a, Wnt-5b and Wnt-4 genes are expressed in chondrogenic regions of the chicken limb: Wnt-5a is expressed in the perichondrium, Wnt-5b is expressed in a subpopulation of prehypertrophic chondrocytes and in the outermost cell layer of the perichondrium, and Wnt-4 is expressed in cells of the joint region. Misexpression experiments demonstrate that two of these Wnt molecules, Wnt-5a and Wnt-4, have opposing effects on the differentiation of chondrocytes and that these effects are mediated through divergent signaling pathways. Specifically, Wnt-5a misexpression delays the maturation of chondrocytes and the onset of bone collar formation, while Wnt-4 misexpression accelerates these two processes. Misexpression of a stabilized form of beta-catenin also results in accelerated chondrogenesis, suggesting that a beta-catenin/TCF-LEF complex is involved in mediating the positive regulatory effect of Wnt-4. A number of the genes involved in Wnt signal tranduction, including two members of the Frizzled gene family, which are believed to encode Wnt-receptors, show very dynamic and distinct expression patterns in cartilaginous elements of developing chicken limbs. Misexpression of putative dominant-negative forms of the two Frizzled proteins results in severe shortening of the infected cartilage elements due to a delay in chondrocyte maturation, indicating that an endogenous Wnt signal does indeed function to promote chondrogenic differentiation.

Animals↗
PubMed1999

A novel molecular mechanism modulating osteoclast differentiation and function.

Osteoclasts, the multinucleated giant cells that resorb bone, develop from hematopoietic cells of the monocyte/ macrophage lineage. Osteoblasts, as well as bone marrow stromal cells, support osteoclast development through a mechanism of cell-to-cell interaction with osteoclast progenitors. We recently purified and molecularly cloned osteoclastogenesis inhibitory factor (OCIF), which was identical to osteoprotegerin (OPG). OPG/OCIF, a secreted member of the tumor necrosis factor (TNF) receptor family, inhibited differentiation and activation of osteoclasts. A single class of high-affinity binding sites for OPG/OCIF appeared on a mouse bone marrow stromal cell line, ST2, in response to 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] and dexamethasone (Dex). When the binding sites were occupied by OPG/OCIF, ST2 cells failed to support the osteoclast formation from spleen cells. To identify an OPG/OCIF ligand, we screened a cDNA expression library of ST2 cells treated with 1,25(OH)2D3 and Dex using OPG/OCIF as a probe. The cloned molecule was found to be a member of the membrane-associated TNF ligand family, and it induced osteoclast formation from mouse and human osteoclast progenitors in the presence of macrophage colony-stimulating factor (M-CSF) in vitro. Expression of its gene in osteoblasts/stromal cells was up-regulated by osteotropic factors, such as 1,25(OH)2D3, prostaglandin E2 (P(GE2), parathyroid hormone (PTH), and interleukin (IL)-11. A polyclonal antibody against this protein, as well as OPG/OCIF, negated not only the osteoclastogenesis induced by the protein, but also bone resorption elicited by various osteotropic factors in a fetal mouse long bone culture system. These findings led us to conclude that the protein is osteoclast differentiation factor (ODF), a long sought-after ligand that mediates an essential signal to osteoclast progenitors for their differentiation into active osteoclasts. Recent analyses of ODF receptor demonstrated that RANK, a member of the TNF receptor family, is the signaling receptor for ODF in osteoclastogenesis, and that OPG/OCIF acts as a decoy receptor for ODF to compete against RANK. The discovery of ODF, OPG/OCIF, and RANK opens a new era in the investigation of the regulation of osteoclast differentiation and function.

Animals↗
PubMed1997

Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2.

The nfkb1 and nfkb2 genes encode closely related products regulating immune and inflammatory responses. Their role during development and differentiation remains unclear. The generation of nfkb1 null mice (p50-/-) resulted in altered immune responses, but had no effect on development. Similarly, nfkb2 knockout mice (p52-/-) did not show developmental defects (J.C. et al., manuscript submitted). We have investigated the potential for in vivo compensatory functions of these genes by generating double-knockout mice. The surprising result was that the animals developed osteopetrosis because of a defect in osteoclast differentiation, suggesting redundant functions of NF-kappaB1 and NF-kappaB2 proteins in the development of this cell lineage. The osteopetrotic phenotype was rescued by bone marrow transplantation, indicating that the hematopoietic component was impaired. These results define a new mouse osteopetrotic mutant and implicate NF-kappaB proteins in bone development, raising new directions in the treatment of bone disorders.

Animals↗
PubMed1994

Normal long bone growth and development in type X collagen-null mice.

To investigate the role of type X collagen in skeletal development, we have generated type X collagen-null mice. Surprisingly, mice without type X collagen were viable and fertile and had no gross abnormalities in long bone growth or development. No differences were detected between the type X collagen-null mice and controls when growth plates of both newborn and 3-week old mice were examined by histology and by immunostaining for extracellular matrix components of bone including osteopontin, osteocalcin and type II collagen. Our results suggest that type X collagen is not required for long bone development. However, mice and humans with dominant acting type X collagen mutations have bone abnormalities, suggesting that only the presence of abnormal type X collagen can modify bone growth and development.

Animals↗
PubMed2004

Grafting RGD containing peptides onto hydroxyapatite to promote osteoblastic cells adhesion.

Ceramics possess osteoconductive properties but exhibit no intrinsic osteoinductive capacity. Consequently, they are unable to induce new bone formation in extra osseous sites. In order to develop bone substitutes with osteogenic properties, one promising approach consists of creating hybrid materials by associating in vitro biomaterials with osteoprogenitor cells. With this aim, we have developed a novel strategy of biomimetic modification to enhance osseointegration of hydroxyapatite (HA) implants. RGD-containing peptides displaying different conformations (linear GRGDSPC and cyclo-DfKRG) were grafted onto HA surface by means of a three-step reaction procedure: silanisation with APTES, cross-linking with N-succinimidyl-3-maleimidopropionate and finally immobilisation of peptides thanks to thiol bonding. Whole process was performed in anhydrous conditions to ensure the reproducibility of the chemical functionalisation. The three-step reaction procedure was characterised by high resolution X-ray photoelectron spectroscopy. Efficiency of this biomimetic modification was finally demonstrated by measuring the adhesion of osteoprogenitor cells isolated from HBMSC onto HA surface.

Amino Acid Sequence↗
PubMed1989

Effect of swimming on bone growth and development in young rats.

The effect of chronic swimming on bone modelling was studied. Forty female Sabra rats (5 weeks old) were randomly assigned to the following experimental groups: 30 rats were trained to swim (water bath 35 +/- 1 degree C, one h daily, five times a week) for 20 weeks--20 of them loaded with lead weights (1% body weight) while the rest (10 animals) swam load free. Ten sedentary rats matched for age and weight served as controls. At the end of the twenty-week swimming period, all rats were sacrificed, both humeri bones were dissected and prepared for the following examinations: morphometric, bone density (BD), bone mineral content (BMC), compression tests and cross-sectional geometrical parameters, histomorphometry and biochemical analysis of minerals (Ca, Pi, Mg, Zn). All measured parameters were found to be significantly higher (P less than 0.05) in the swimming rats irrespective of load, as compared with the controls. Bone weight was higher by 19%, bone volume by 11%, bone length by 2.8%, cortical area by 16%, BD by 7% and BMC by 15%. The compression breaking force at the distal shaft of the humerus was higher by 24% in the trained group, while the ultimate compressive stress was not significantly different. Maximal and minimal moment of inertia at the distal diaphysis were 33.4 and 40% higher, respectively, for the swimming groups than the controls. Ca, Pi, Mg and Zn levels per total humeral bone were significantly higher in the exercising rats. The histomorphometry and cross-sectional data emphasize longitudinal and transversal growth. These data indicate that swimming exercise exerts a positive effect on bone growth and development in young rats.

Animals↗
PubMed2000

Bone morphogenetic protein-4 regulates its own expression in cultured osteoblasts.

During development, bone morphogenetic proteins (BMPs) induce the differentiation of mesenchymal progenitor cells to enter into the osteoblastic lineage, and BMPs enhance osteoblastic function. BMPs and noggin, a specific binding protein that blocks BMP actions, are expressed by osteoblastic cells but there is limited information about regulation of BMP synthesis in skeletal cells. We tested for the expression and regulation of BMP-4 in cultures of osteoblast-enriched cells from 22-day fetal rat calvariae (Ob cells). BMP-4 caused a short-lived increase in BMP-4 mRNA followed by a marked inhibition of BMP-4 expression. The stimulatory effect was transcriptional, as determined by nuclear run-on assays, whereas the inhibitory effect was transcriptional and posttranscriptional, because longer BMP-4 exposure decreased its rate of transcription and shortened the half-life of BMP-4 mRNA in transcriptionally arrested Ob cells. BMP-2 and BMP-6 also inhibited BMP-4 mRNA levels. Transforming growth factor beta1 increased, whereas fibroblast growth factor-2, platelet-derived growth factor BB, and insulin-like growth factor I decreased BMP-4 mRNA in Ob cells. BMP-2 also was expressed by Ob cells and it was downregulated by BMP-2, BMP-4, and BMP-6. Noggin increased BMP-4 transcripts, suggesting autocrine control of BMP-4 expression. In conclusion, BMP-4 inhibits its own expression in Ob cells, a mechanism to limit BMP availability to osteoblasts.

Animals↗
PubMed1991

Modulation of osteogenesis in fetal bone rudiments by mechanical stress in vitro.

Studies of organ cultures of developing bone subjected to intermittent mechanical stress are reviewed. Mineral metabolism in these bones is modulated by exposure to dynamic stress of physiological magnitude. Finite element stress analysis of long bone rudiments shows that hydrostatic pressure during organ culture produces significant shear stresses at mineralized/non-mineralized tissue interfaces, in addition to dilatational stress. Both matrix producing cells (chondrocytes, osteoblasts) and matrix resorbing cells (osteoclasts) are affected by mechanical stress in vitro. The organ culture model offers certain opportunities for studying effects of mechanical stress on skeletal tissue at the cell and tissue level.

Animals↗
PubMed2001

Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis.

The receptor activator of NF-kappaB (RANKL) is the essential signal required for full osteoclast (OC) development, activation, and survival. RANKL is highly expressed in areas of trabecular bone remodeling and inflammatory bone loss, is increased on marrow stromal cells or osteoblasts by osteotropic hormones or cytokines, and is neutralized by osteoprotegerin (OPG), a soluble decoy receptor also crucial for preventing arterial calcification. Vascular endothelial cells (VEC) are critically involved in bone development and remodeling and influence OC recruitment, formation, and activity. Although OCs develop and function in close association with bone VEC and sinusoids, signals mediating their interactions are not well known. Here, we show for the first time that human microvascular endothelial cells (HMVEC) express transcripts for both RANKL and OPG; inflammatory cytokines tumor necrosis factor-alpha and interleukin-1alpha elevate RANKL and OPG expression 5-40-fold in HMVEC (with an early OPG peak that declines as RANKL rises), and RANKL protein increases on the surface of tumor necrosis factor-alpha-activated HMVEC. Cytokine-activated HMVEC promoted the formation, fusion, and bone resorption of OCs formed in co-cultures with circulating human monocytic precursors via a RANKL-mediated mechanism fully antagonized by exogenous OPG. Furthermore, paraffin sections of human osteoporotic fractured bone exhibited increased RANKL immunostaining in vivo on VEC located near resorbing OCs in regions undergoing active bone turnover. Therefore, cytokine-activated VEC may contribute to inflammatory-mediated bone loss via regulated production of RANKL and OPG. VEC-derived OPG may also serve as an autocrine signal to inhibit blood vessel calcification.

Base Sequence↗
PubMed1996

Unrelated donor bone marrow transplantation for Fanconi anemia.

Patients with Fanconi anemia (FA) commonly develop bone marrow failure, which may evolve to myelodysplasia or acute myeloid leukemia (AML). Treatment of these patients is complicated by their marked hypersensitivity to DNA cross-linking agents. In this report we describe the results of allogeneic unrelated donor bone marrow transplantation in seven FA patients, using a low-dose cyclophosphamide (40 mg/kg) and TBI (400-450 cGy) conditioning regimen. Two patients had bone marrow failure with normal chromosomes and no dysplasia prior to transplant. The remaining five had clonal chromosomal abnormalities. One patient had refractory anemia with excess blasts in transformation and two had early AML with 20 and 25% blasts, respectively. Two patients died early (before day 28) without hematological evidence of engraftment, one of veno-occlusive disease and one of infection (fungal). Four of the remaining five patients achieved sustained engraftment after the first marrow infusion; one patient had secondary graft failure requiring repeat marrow infusion but subsequently achieved engraftment. Of five evaluable patients, three had mild (grades I-II) acute GVHD and two had grade IV GVHD, which was fatal in both cases. Two of three evaluable surviving patients have chronic GVHD controlled with immunosuppression. Three patients survive 9 months to 3 years post-unrelated donor BMT: two who had early leukemia and one with severe aplasia at the time of transplant. These data indicate that unrelated donor BMT can be performed successfully in FA patients using cyclophosphamide 40 mg/kg and TBI 400 to 450 cGy, even after evolution to early leukemia. However, significant problems with both GVHD and engraftment remain. Future studies will evaluate the role of T cell depletion in improving the results of unrelated donor marrow transplantation in FA patients.

Adolescent↗
PubMed2001

Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction.

Recent studies in transgenic mice have demonstrated that PTH-related protein (PTHrP), signaling through the type 1 PTH/PTHrP receptor (PTHR1), regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Recently, it has been shown that loss-of-function mutations in the PTHR1 gene result in a rare, lethal form of dwarfism known as Blomstrand chondrodysplasia. These patients suffer from severe defects in endochondral bone formation, but abnormalities in breast and tooth development have not been reported. To ascertain whether PTHrP signaling was important to human breast and tooth development, we studied two fetuses with Blomstrand chondrodysplasia. These fetuses lack nipples and breasts. Developing teeth were present, but they were severely impacted within the surrounding alveolar bone, leading to distortions in their architecture and orientation. Compatible with the involvement of PTHR1 and PTHrP in human breast and tooth morphogenesis, both were expressed within the developing breasts and teeth of normal human fetuses. Therefore, impairment of the PTHrP/PTHR1 signaling pathway in humans is associated with severe abnormalities in tooth and breast development. In addition to regulating human bone formation, this signaling pathway is also necessary for the normal development of the human breast and tooth.

Breast↗
PubMed1983

Restricted energy intake and elevated calcium and phosphorus intake for gilts during growth. IV. Characterization of metacarpal, metatarsal, femur, humerus and turbinate bones of sows during three parities.

The effect of early nutrition on subsequent bone development was studied using gilts that had previously been fed ad libitum or 75% ad libitum intake and 100 or 150% National Research Council-recommended daily Ca and P from weaning to 100 kg. During the three-parity reproductive study, sows were fed a 14% protein diet. Metacarpals and metatarsals were taken from sows culled due to lameness or failure to breed and from sows after completing three parities. Femur and humerus articular cartilage and turbinates were described at necropsy. Metacarpals and metatarsals were heavier and tended to have thicker walls when sows were previously fed ad libitum or fed 150% Ca and P. Energy intake produced the greater response. Metacarpal breaking strength was greatest for sows previously fed ad libitum. Metatarsals were not affected by energy intake. Stiffness, Young's modulus of elasticity (YME) and flexural modulus for metacarpals and metatarsals were not affected by energy intake. Previously fed Ca and P intakes did not affect any of the mechanical bone characteristics. Metacarpals were heavier, had a greater breaking strength, were more elastic and exhibited slightly less resistance to bending than the metatarsals. The ether extract, ash, Ca and P content and the Ca:P ratio of metacarpals and metatarsals were not affected by previously fed energy or Ca and P intakes. The ether extract content tended to decrease and the ash, Ca and P content tended to increase with age. Articular cartilage and turbinate scores were not influenced by previously fed energy or Ca and P intakes. The YME and flexural modulus were the only bone characteristics that were even poorly correlated (average r = .25) with soundness scores, suggesting that high values result in poorer soundness scores. Energy and Ca and P intakes during growth and development had only minimal effects on bone characteristics and no apparent effect on structural soundness and longevity of sows kept for three parities.

Animals↗